CN109134222B - Preparation method of 2-hydroxy isopropyl substituted acetophenone - Google Patents
Preparation method of 2-hydroxy isopropyl substituted acetophenone Download PDFInfo
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- CN109134222B CN109134222B CN201811072389.5A CN201811072389A CN109134222B CN 109134222 B CN109134222 B CN 109134222B CN 201811072389 A CN201811072389 A CN 201811072389A CN 109134222 B CN109134222 B CN 109134222B
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Abstract
The present application relates to a method for the synthesis of 2-hydroxyisopropyl-substituted acetophenones comprising S1: reacting methyl acetylbenzoate and ethylene glycol in the presence of an organic solvent and a catalyst at a temperature of 130 ℃ and 140 ℃ to generate a first reaction mixture containing an intermediate; s2: cooling the first reaction mixture to room temperature, and purifying the first reaction mixture to obtain an intermediate; s3: dropwise adding the tetrahydrofuran solution of the intermediate into the tetrahydrofuran solution of methyl magnesium bromide at a temperature of-5 to 0 ℃ in an inert atmosphere to generate a second reaction mixture containing the 2-hydroxyisopropyl-substituted acetophenone; and S4: purifying the second reaction mixture to obtain the 2-hydroxyisopropyl-substituted acetophenone; wherein the methyl acetylbenzoate comprises methyl 4-acetylbenzoate or methyl 3-acetylbenzoate. The method has the advantages of simple and easily-obtained raw materials, simple and convenient preparation process, high yield and small environmental pollution.
Description
Technical Field
The application relates to the technical field of organic synthesis. In particular, the application relates to a preparation method of 2-hydroxy isopropyl substituted acetophenone.
Background
The 2-hydroxyl isopropyl substituted acetophenone is mainly used in the field of biomedicine and is an important intermediate monomer.
An organism must synthesize nucleotides to divide its cells, and inosine-5' -monophosphate dehydrogenase (IMPDH) is an enzyme for guanine nucleotide biosynthesis. And some drugs synthesized with (2-hydroxyisopropyl) acetophenone and other compounds can be used as inhibitors of IMPDH, can selectively inhibit parasitic IMPDH and host IMPDH, and can treat various parasitic and bacterial infections in mammals and birds. Therefore, (2-hydroxy isopropyl) acetophenone is an important intermediate monomer of medicines, and can be used for preparing antiviral agents, anti-inflammatory agents, antimicrobial agents and immunosuppressants. The preparation method of the compound also becomes the key point of research of people, and a simple, convenient and economic synthetic route can be developed to bring certain social and economic benefits.
The current synthesis method for 2-hydroxyisopropyl-substituted acetophenone mainly uses ketone protective agent, for example, Kenzo Yahata et al uses trimethylsilyl trifluoromethanesulfonate (TMSOTf), triphenylphosphine PPh3 or triethylphosphine PEt3As a ketone protective agent, the compound is reacted with a format reagent MeMgBr to prepare the 4- (2-hydroxyl isopropyl) acetophenone, but the ketone protective agent contains phosphorus, is not environment-friendly and has higher cost, and industrial mass production is not economical.
For this reason, there is a strong need in the art for a novel method for preparing 2-hydroxyisopropyl-substituted acetophenones, which solves at least the above problems.
Disclosure of Invention
The present application aims to solve the above-mentioned problems of the prior art by providing a novel method for preparing 2-hydroxyisopropyl-substituted acetophenones, for example, 4- (2-hydroxyisopropyl) acetophenone and 3- (2-hydroxyisopropyl) acetophenone.
In order to solve the above technical problems, the present application provides the following technical solutions.
In a first aspect, the present application provides a process for the preparation of 2-hydroxyisopropyl substituted acetophenones, characterized in that the process comprises:
s1: reacting methyl acetylbenzoate and ethylene glycol in the presence of at least one organic solvent and a catalyst at a temperature of 130 ℃ and 140 ℃ to form a first reaction mixture containing an intermediate having the structure shown in the following formula I,
s2: cooling the first reaction mixture to room temperature, and purifying the first reaction mixture to obtain an intermediate with a structure shown in a formula I;
s3: dripping the tetrahydrofuran solution of the intermediate into the tetrahydrofuran solution of methyl magnesium bromide at the temperature of between 5 ℃ below zero and 0 ℃ in the environment of inert atmosphere to generate a second reaction mixture containing the 2-hydroxy isopropyl substituted acetophenone with the structure shown in the formula II,
s4: purifying the second reaction mixture to obtain the 2-hydroxyisopropyl-substituted acetophenone;
wherein the methyl acetylbenzoate comprises methyl 4-acetylbenzoate or methyl 3-acetylbenzoate.
In one embodiment of the first aspect, the organic solvent comprises toluene; and/or, the catalyst comprises p-toluenesulfonic acid.
In one embodiment of the first aspect, the method comprises adding the ethylene glycol to the mixed solution of the methyl acetylbenzoate, the catalyst and the organic solvent in three times at the temperature of 130-140 ℃, and carrying out a thermal reflux reaction for 2-3 hours to generate the first reaction mixture.
In one embodiment of the first aspect, the process comprises using a water trap pre-filled with the organic solvent for separating the water produced by the reaction of the methyl acetylbenzoate and the ethylene glycol to increase the yield of the first reaction mixture.
In one embodiment of the first aspect, purifying the first reaction mixture comprises:
a. adding a saturated sodium carbonate solution to neutralize the first reaction mixture;
b. adding ethyl acetate, stirring, standing for layering, and removing water phase;
c. testing the pH value of the organic phase: if the pH is not 7, washing the organic phase with water until the pH is 7; and
d. concentrating the organic phase at a temperature of 30-40 deg.C, and purifying the concentrated organic phase using a chromatography column to obtain the intermediate.
In one embodiment of the first aspect, purifying the concentrated organic phase using the chromatography column comprises:
adding silica gel into the chromatographic column;
adding ethyl acetate into the concentrated organic phase to dissolve the organic phase, adding silica gel, uniformly stirring, and performing rotary evaporation at the temperature of 30-40 ℃ to obtain a third reaction mixture containing the intermediate;
sequentially adding neutral alumina, the third reaction mixture and neutral alumina into the chromatographic column filled with silica gel; and
after the chromatographic column is washed by petroleum ether, washing the chromatographic column by using a washing liquid, and concentrating a solvent to obtain the intermediate, wherein the washing liquid comprises a solvent with a volume ratio of 50: 1 petroleum ether and ethyl acetate.
In one embodiment of the first aspect, the method comprises maintaining the temperature at-5 to 0 ℃ by a dry ice alcohol bath, adding the tetrahydrofuran solution of the intermediate dropwise into the tetrahydrofuran solution of the methyl magnesium bromide under a nitrogen atmosphere, removing the dry ice alcohol bath, and naturally raising the temperature for 2 to 3 hours to generate the second reaction mixture.
In one embodiment of the first aspect, purifying the second reaction mixture comprises:
dropwise adding water to the second reaction mixture at the temperature of 10-20 ℃ to quench the reaction;
adjusting the pH of the quenched second reaction mixture to 1 by using a 10% hydrochloric acid solution, and stirring at room temperature for 2 hours to obtain a fourth reaction mixture;
extracting the fourth reaction mixture twice with ethyl acetate and combining the organic phases;
adding anhydrous sodium sulfate into the combined organic phase, drying and filtering; and
and (3) after spin-drying the filtrate, purifying by using a chromatographic column to obtain the 2-hydroxy isopropyl substituted acetophenone.
In one embodiment of the first aspect, purifying using the chromatography column comprises:
adding silica gel into the chromatographic column;
spin-drying the filtrate, adding ethyl acetate to dissolve the filtrate, adding silica gel, uniformly stirring, and then spin-steaming at the temperature of 30-40 ℃ to obtain a fifth reaction mixture containing the 2-hydroxyisopropyl-substituted acetophenone;
sequentially adding neutral alumina, the fifth reaction mixture and neutral alumina into the chromatographic column filled with silica gel; and
and (3) after the chromatographic column is washed by petroleum ether, washing the chromatographic column by using at least one washing liquid, and concentrating a solvent to obtain the 2-hydroxy isopropyl substituted acetophenone.
In one embodiment of the first aspect, the at least one rinsing liquid is selected from the group consisting of 30: 1, petroleum ether and ethyl acetate solution with the volume ratio of 20: 1, petroleum ether and ethyl acetate solution with the volume ratio of 10:1 of petroleum ether and ethyl acetate solution and the volume ratio of 5:1 petroleum ether and ethyl acetate.
Compared with the prior art, the method for preparing the 2-hydroxyisopropyl-substituted acetophenone simply and efficiently has the advantages that the simple and easily obtained ethylene glycol is adopted as the ketone protective agent, the 2-hydroxyisopropyl-substituted acetophenone is prepared by reacting the Grignard reagent methyl magnesium bromide with the intermediate product, industrial mass production can be realized, the production cost is reduced, the method is economical and practical, and the ketone protective agent does not contain phosphorus and has small environmental pollution.
Drawings
FIG. 1 shows a NMR spectrum of 4- (2-hydroxyisopropyl) acetophenone according to example 1.
FIG. 2 shows a NMR spectrum of 3- (2-hydroxyisopropyl) acetophenone according to example 2.
Detailed Description
Unless otherwise indicated, implied from the context, or customary in the art, all parts and percentages herein are by weight and the testing and characterization methods used are synchronized with the filing date of the present application. Where applicable, the contents of any patent, patent application, or publication referred to in this application are incorporated herein by reference in their entirety and their equivalent family patents are also incorporated by reference, especially as they disclose definitions relating to synthetic techniques, products and process designs, polymers, comonomers, initiators or catalysts, and the like, in the art. To the extent that a definition of a particular term disclosed in the prior art is inconsistent with any definitions provided herein, the definition of the term provided herein controls.
The numerical ranges in this application are approximations, and thus may include values outside of the ranges unless otherwise specified. A numerical range includes all numbers from the lower value to the upper value, in increments of 1 unit, provided that there is a separation of at least 2 units between any lower value and any higher value. For example, if a compositional, physical, or other property (e.g., molecular weight, melt index, etc.) is recited as 100 to 1000, it is intended that all individual values, e.g., 100, 101,102, etc., and all subranges, e.g., 100 to 166,155 to 170,198 to 200, etc., are explicitly recited. For ranges containing a numerical value less than 1 or containing a fraction greater than 1 (e.g., 1.1, 1.5, etc.), then 1 unit is considered appropriate to be 0.0001, 0.001, 0.01, or 0.1. For ranges containing single digit numbers less than 10 (e.g., 1 to 5), 1 unit is typically considered 0.1. these are merely specific examples of what is intended to be expressed and all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application.
When used with respect to chemical compounds, the singular includes all isomeric forms and vice versa (e.g., "hexane" includes all isomers of hexane, individually or collectively) unless expressly specified otherwise. In addition, unless explicitly stated otherwise, the use of the terms "a", "an" or "the" are intended to include the plural forms thereof.
The terms "comprising," "including," "having," and derivatives thereof do not exclude the presence of any other component, step or procedure, and are not intended to exclude the presence of other elements, steps or procedures not expressly disclosed herein. To the extent that any doubt is eliminated, all compositions herein containing, including, or having the term "comprise" may contain any additional additive, adjuvant, or compound, unless expressly stated otherwise. Rather, the term "consisting essentially of … …" excludes any other components, steps or processes from the scope of any of the terms hereinafter recited, insofar as such terms are necessary for performance. The term "consisting of … …" does not include any components, steps or processes not specifically described or listed. Unless explicitly stated otherwise, the term "or" refers to the listed individual members or any combination thereof.
Definition of terms
As used herein, the term "yield" refers to the amount of product obtained in a chemical reaction. The yield is usually expressed as a percentage of the theoretical yield of the reaction.
As used herein, the term "chromatography" is the subject of gel chromatography techniques, typically using glass or plexiglass tubes. A chromatographic method for separating components of a sample mixture by their different partition coefficients in a stationary phase and a mobile phase.
As used herein, the term "water diversion" is the removal of water produced by distillation of an azeotropic mixture using a water trap to continuously return the organic layer above the water layer produced by the reaction to the reaction flask.
The application discloses a preparation method of 2-hydroxy isopropyl substituted acetophenone, which comprises the following steps:
the first step is ketone protection: adding ethylene glycol into a mixed solution of methyl acetylbenzoate, a catalyst and an organic solvent for three times at the temperature of 130 ℃ and 140 ℃, and carrying out thermal reflux reaction for 2-3 hours to generate a first reaction mixture containing a structure shown as a formula I.
In one embodiment, the methyl acetylbenzoate may comprise methyl 4-acetylbenzoate or methyl 3-acetylbenzoate.
It will be appreciated by those skilled in the art that in formula I, the methyl formate group may be in the ortho, para or meta position of the phenyl ring.
By applying the method, the simple and easily obtained ethylene glycol is used as the ketone protective agent, so that the production cost can be reduced. And the ketone protective agent does not contain phosphorus and has small pollution to the environment.
In some embodiments, the thermal reflux reactor comprises a water trap pre-filled with an organic solvent to separate the water produced by the reaction of methyl acetylbenzoate and ethylene glycol and facilitate the reversible reaction toward the formation of formula I, thereby increasing the yield of the first reaction mixture.
In some embodiments, the organic solvent comprises toluene and the catalyst comprises p-toluenesulfonic acid (TsOH).
And cooling the generated first reaction mixture to room temperature, and purifying the first reaction mixture to obtain a first reaction intermediate with a structural formula shown in the formula I. In some embodiments, purifying the first reaction mixture comprises: firstly, adding saturated sodium carbonate solution to neutralize the first reaction mixture; secondly, adding ethyl acetate, stirring, standing for layering and removing a water phase; subsequently, the organic phase was tested for pH: if the pH is not 7, the organic phase is washed with water until the pH is 7; finally, the organic phase is concentrated at a temperature of 30-40 ℃, and the concentrated organic phase is purified using a chromatographic column to obtain a first reaction intermediate.
In some embodiments, purifying using a chromatography column comprises: adding silica gel into the chromatographic column; adding the concentrated organic phase into ethyl acetate to dissolve, adding silica gel, uniformly stirring, and performing rotary evaporation at the temperature of 30-40 ℃ to obtain a third reaction mixture containing an intermediate; sequentially adding neutral alumina, the third reaction mixture and neutral alumina into the chromatographic column filled with silica gel; and after the chromatographic column is flushed by petroleum ether, flushing the chromatographic column by using a flushing liquid, and concentrating the solvent to obtain an intermediate, wherein the flushing liquid comprises a solvent with a volume ratio of 50: 1 petroleum ether and ethyl acetate.
The second step is main reaction and deprotection: and (3) dropwise adding the tetrahydrofuran solution of the intermediate into the tetrahydrofuran solution of methyl magnesium bromide at the temperature of-5-0 ℃ in an inert atmosphere, such as a nitrogen atmosphere, removing the dry ice alcohol bath, and naturally heating for reaction for 2-3 hours to generate a second reaction mixture containing the 2-hydroxyisopropyl substituted acetophenone shown in the formula II.
It will be appreciated by those skilled in the art that in formula II, the 2-hydroxyisopropyl group may be in the ortho, para or meta position of the phenyl ring.
And purifying the generated second reaction mixture to obtain the 2-hydroxy isopropyl substituted acetophenone with the structural formula shown as the formula II. In some embodiments, purifying the second reaction mixture comprises: dropwise adding water into the second reaction mixture at the temperature of 10-20 ℃ to quench the reaction; adjusting the pH value of the quenched second reaction mixture to 1 by using a 10% hydrochloric acid solution, and stirring at room temperature for 2 hours to obtain a fourth reaction mixture; extracting the fourth reaction mixture twice with ethyl acetate and combining the organic phases; adding anhydrous sodium sulfate into the combined organic phase, drying and filtering; and after the filtrate is dried by spinning, purifying by using a chromatographic column to obtain the 2-hydroxyl isopropyl substituted acetophenone.
In some embodiments, purifying using a chromatography column comprises: adding silica gel into the chromatographic column; spin-drying the filtrate, adding ethyl acetate to dissolve, adding silica gel, uniformly stirring, and spin-steaming at 30-40 ℃ to obtain a fifth reaction mixture containing 2-hydroxyisopropyl-substituted acetophenone; sequentially adding neutral alumina, the fifth reaction mixture and neutral alumina into the chromatographic column filled with the silica gel; and after the chromatographic column is washed by petroleum ether, washing the chromatographic column by at least one washing liquid, and concentrating the solvent to obtain the 2-hydroxy isopropyl substituted acetophenone.
In some embodiments, the at least one rinse solution is selected from the group consisting of 30: 1, petroleum ether and ethyl acetate solution with the volume ratio of 20: 1, petroleum ether and ethyl acetate solution with the volume ratio of 10:1 of petroleum ether and ethyl acetate solution and the volume ratio of 5:1 petroleum ether and ethyl acetate.
The method has the advantages that the lattice reagent methyl magnesium bromide is used for the main reaction to react with the intermediate product to prepare the 2-hydroxy isopropyl substituted acetophenone, the process is simple, the reaction condition is mild, the yield of the two-step method is about more than 90%, industrial mass production of the 2-hydroxy isopropyl substituted acetophenone can be realized, and the method is economical and practical.
Examples
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. The reagents and raw materials used are commercially available unless otherwise specified. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
In this example, 4- (2-hydroxyisopropyl) acetophenone was prepared by the following method.
A100 mL one-neck flask was charged with 5g of methyl 4-acetylbenzoate, 50mL of toluene, and 0.5g of TsOH. H2O, and a water separator previously filled with toluene was attached to the reaction apparatus. The reaction was heated under reflux at a temperature of 135 ℃ in an oil bath for 2 to 3 hours, and 3.5g of ethylene glycol was added in three portions to a single-necked flask during the reaction, to cause the reaction as in the reaction formula (1).
Cooled to room temperature, and 50mL of saturated sodium carbonate solution was added to the flask for neutralization and stirred for 5 min. 100mL of ethyl acetate was added, the mixture was extracted with stirring, and the mixture was allowed to stand for separation and the aqueous phase was removed. The organic phase was tested for pH and if not neutral, the organic phase was washed with water to a pH of 7. The organic phase was concentrated at a temperature of 30-40 ℃ to give a pale yellow oil.
Using a 50cm column, about 140g of silica gel (200-. sup. & ltSUB- & gt, 300M) was added by wet column packing. Dissolving the yellowish oily substance with small amount of ethyl acetate, adding 8g of silica gel, stirring, and rotary evaporating at 30-40 deg.C to remove the solvent to obtain silica gel powder containing intermediate. Adding 2g of neutral alumina (for preventing the materials from being dispersed) into a chromatographic column filled with silica gel, adding uniformly mixed silica gel powder containing an intermediate, then adding 2g of neutral alumina, and finishing the charging. When the catalyst passes through the column, a small amount of petroleum ether is firstly used for washing, and then the volume ratio of the petroleum ether to the petroleum ether is 50: 1 Petroleum Ether (PE) and Ethyl Acetate (EA) solution, and the solvent was concentrated to give a near colorless liquid as the first step intermediate.
A dry 250mL four-necked flask was purged with nitrogen for 5-10min, kept under an inert atmosphere, and 55mL of a methylmagnesium bromide solution was added to the four-necked flask with a syringe. And (3) reducing the reaction temperature of the four-mouth bottle to-5 ℃ by using a dry ice alcohol bath, slowly injecting the first-step intermediate which is diluted by Tetrahydrofuran (THF) in advance into the four-mouth bottle, removing the dry ice alcohol bath after the dropwise addition is finished, and naturally heating to react for 2-3 hours to generate the reaction shown in the reaction formula (2).
At the temperature of 10-20 ℃, 30ml of water is dripped into a four-mouth bottle to quench the reaction, the system becomes turbid, viscous solid is generated, the pH value of the quenched solution is adjusted to 1 by using about 20ml of 10% HCl solution, the solution is clarified, and the solution is stirred for 2 hours at room temperature.
The stirred solution was extracted twice with 100mL of ethyl acetate and the organic phases obtained from the extraction were combined (thin layer chromatography of the aqueous phase showed no product). And adding 10g of anhydrous sodium sulfate into the combined organic phase, drying, filtering, and spin-drying the filtrate to obtain a yellow crude liquid.
Using a 50cm column, about 140g of silica gel (200-. sup. & ltSUB- & gt, 300M) was added by wet column packing. Dissolving the yellow liquid crude product with a small amount of ethyl acetate, adding 5g of silica gel, stirring uniformly, and performing rotary evaporation at 30-40 ℃ to remove the solvent to obtain silica gel powder containing the 4- (2-hydroxy isopropyl) acetophenone crude product. Adding 2g of neutral alumina (for preventing the materials from being dispersed) into a chromatographic column filled with silica gel, adding uniformly mixed silica gel powder containing a crude product of 4- (2-hydroxy isopropyl) acetophenone, adding 2g of neutral alumina, and finishing charging. When the column passes through the column, a small amount of petroleum ether is used for washing, and then 1L of the petroleum ether with the volume ratio of 30: 1 Petroleum Ether (PE) and Ethyl Acetate (EA) solution, 1L volume ratio 20: 1 Petroleum Ether (PE) and Ethyl Acetate (EA) solution, 2L volume ratio 10:1 Petroleum Ether (PE) and Ethyl Acetate (EA) solution and 2L volume ratio of 5:1 Petroleum Ether (PE) and Ethyl Acetate (EA) solution, and the solvent was concentrated to give 3.1g of pale yellow crystals as 4- (2-hydroxyisopropyl) acetophenone. The molar yield for this embodiment is 90.85%.
The NMR spectrum of the resulting product was measured in DMSO solvent and is shown in FIG. 1. As is clear from FIG. 1, 4- (2-hydroxyisopropyl) acetophenone was prepared.
Example 2
In this example, 3- (2-hydroxyisopropyl) acetophenone was prepared by the following method.
The method comprises the following steps of adopting a process similar to that of example 1, wherein in the first step, ketone protection is carried out, methylbenzene is used as a solvent, TsOH is used as a catalyst, 3-acetylmethyl benzoate and ethylene glycol carry out water division reaction for 3-4 hours at the external temperature of 135 ℃, a sodium carbonate solution is neutralized, ethyl acetate is extracted, and the ethyl acetate is concentrated and purified by a column; and (2) a second step of main reaction and deprotection, namely, dripping a THF solution of the intermediate in the first step into a THF solution of methyl magnesium bromide at a temperature of-5-0 ℃, reacting for 2-3 h, adding water for quenching, adding 10% HCL to adjust the pH value to 1, stirring at room temperature, extracting with ethyl acetate, concentrating, and purifying by a column to obtain a qualified product.
The synthetic route of this example is as follows:
the first step is as follows:
adding 5g of methyl 3-acetylbenzoate, 50mL of toluene, 4.34g of ethylene glycol and 0.5g of TsOH & H2O into a 100mL single-neck bottle, adding a water separator (filling the water separator with toluene in advance), heating and refluxing for 2-3H at 130-140 ℃ in an oil bath, sampling, finishing the reaction, and cooling to room temperature.
Adding 50ml of saturated sodium carbonate solution, stirring for 5min, then adding 100ml of ethyl acetate, fully stirring and extracting, standing for layering, removing a water phase, washing an organic phase to be neutral, and concentrating the solvent at 30-40 ℃ to obtain a crude product which is a light yellow oily substance.
Adding 140g of silica gel (200-300M) into a 50cm chromatographic column by a wet column packing method, dissolving a crude product by using a small amount of ethyl acetate, adding 8g of silica gel, uniformly stirring, performing rotary evaporation at 30-40 ℃ to remove the solution, adding 2g of neutral alumina (for preventing the material from being dispersed) into the chromatographic column packed with the silica gel, adding uniformly mixed crude silica gel powder, adding 2g of neutral alumina, and finishing the loading. And (3) washing with a small amount of petroleum ether when passing through the column, and then carrying out PE: EA is 50: 1 washing the product, and concentrating the solvent to obtain a first step intermediate which is a white crystal.
The second step is that:
introducing nitrogen into a dry 250mL four-mouth bottle for 5-10min, adding 55mL of methyl magnesium bromide solution by using an injector, cooling the dry ice alcohol to-5 ℃, slowly injecting the intermediate 1 diluted by THF into the four-mouth bottle, naturally heating to react for 2-3 h after the dropwise addition is finished, controlling the temperature to be 1, and finishing the reaction.
And (3) dropwise adding 30ml of water at 10-20 ℃ to quench the reaction, wherein the system becomes turbid, a viscous solid is generated, adjusting the pH value to 1 by using about 20ml of 10% HCl, clarifying the solution, stirring at room temperature for 2 hours, sampling, controlling the pH value to 2, and finishing the reaction.
The extraction is carried out twice with 100ml ethyl acetate respectively, the organic phases are combined, the TLC of the water phase shows no product, 10g of anhydrous sodium sulfate is added into the organic phase for drying, the filtration is carried out, and 6.55g of crude yellow liquid is obtained after the filtrate is dried by spinning.
Adding 140g of silica gel (200-300M) into a 50cm chromatographic column by a wet column packing method, dissolving a crude product by using a small amount of ethyl acetate, adding 8g of silica gel, uniformly stirring, performing rotary evaporation at 30-40 ℃ to remove the solution, adding 2g of neutral alumina (for preventing the material from being dispersed) into the chromatographic column packed with the silica gel, adding uniformly mixed crude silica gel powder, adding 2g of neutral alumina, and finishing the loading. The column was first flushed with a small amount of pure petroleum ether and the column was washed with 1 LPE: EA is 30: 1 rinsing, then 1 LPE: EA is 20: 1 rinsing, with 2L PE: wash EA 10:1 to product, with 2 LPE: the product was eluted with EA 5:1 and the solvent was concentrated to give 2.5g of pale yellow crystals. Molar yield: 77.93 percent.
The NMR spectrum of the resulting product was measured in DMSO solvent and is shown in FIG. 2. As is clear from FIG. 1, 3- (2-hydroxyisopropyl) acetophenone was prepared.
The embodiments described above are intended to facilitate the understanding and appreciation of the application by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present application is not limited to the embodiments herein, and those skilled in the art who have the benefit of this disclosure will appreciate that many modifications and variations are possible within the scope of the present application without departing from the scope and spirit of the present application.
Claims (8)
1. A method for preparing 2-hydroxyisopropyl-substituted acetophenone, comprising:
s1: reacting methyl acetylbenzoate and ethylene glycol in the presence of at least one organic solvent and a catalyst at the temperature of 130-140 ℃, wherein the reaction comprises the following steps:
adding the ethylene glycol into the mixed solution of the methyl acetylbenzoate, the catalyst and the organic solvent for three times, and carrying out thermal reflux reaction for 2-3 hours to generate a first reaction mixture containing an intermediate with a structure shown in the following formula I,
s2: cooling the first reaction mixture to room temperature, and purifying the first reaction mixture to obtain an intermediate with a structure shown in formula I, wherein the step of purifying the first reaction mixture comprises the following steps:
a. adding a saturated sodium carbonate solution to neutralize the first reaction mixture;
b. adding ethyl acetate, stirring, standing for layering, and removing water phase;
c. testing the pH value of the organic phase: if the pH is not 7, washing the organic phase with water until the pH is 7; and
d. concentrating the organic phase at a temperature of 30-40 ℃, and purifying the concentrated organic phase with a chromatography column to obtain the intermediate;
s3: dripping the tetrahydrofuran solution of the intermediate into the tetrahydrofuran solution of methyl magnesium bromide at the temperature of between 5 ℃ below zero and 0 ℃ in the environment of inert atmosphere to generate a second reaction mixture containing the 2-hydroxy isopropyl substituted acetophenone with the structure shown in the formula II,
s4: purifying the second reaction mixture to obtain the 2-hydroxyisopropyl-substituted acetophenone;
wherein the methyl acetylbenzoate comprises methyl 4-acetylbenzoate or methyl 3-acetylbenzoate.
2. A method according to claim 1, wherein the organic solvent comprises toluene; and/or, the catalyst comprises p-toluenesulfonic acid.
3. A production process as claimed in claim 1, which comprises using a water separator filled with the organic solvent beforehand for separating water produced by the reaction of the methyl acetylbenzoate and the ethylene glycol to increase the yield of the first reaction mixture.
4. The method of claim 1, wherein purifying the concentrated organic phase using the chromatography column comprises:
adding silica gel into the chromatographic column;
adding ethyl acetate into the concentrated organic phase to dissolve the organic phase, adding silica gel, uniformly stirring, and performing rotary evaporation at the temperature of 30-40 ℃ to obtain a third reaction mixture containing the intermediate;
sequentially adding neutral alumina, the third reaction mixture and neutral alumina into the chromatographic column filled with silica gel; and
after the chromatographic column is washed by petroleum ether, washing the chromatographic column by using a washing liquid, and concentrating a solvent to obtain the intermediate, wherein the washing liquid comprises a solvent with a volume ratio of 50: 1 petroleum ether and ethyl acetate.
5. A production process according to claim 1, which comprises maintaining the temperature at-5 to 0 ℃ by means of a dry ice alcohol bath, adding a tetrahydrofuran solution of the intermediate dropwise to a tetrahydrofuran solution of the methylmagnesium bromide under a nitrogen atmosphere, removing the dry ice alcohol bath, and allowing the mixture to naturally warm up for 2 to 3 hours to produce the second reaction mixture.
6. The method of claim 1, wherein purifying the second reaction mixture comprises:
dropwise adding water to the second reaction mixture at the temperature of 10-20 ℃ to quench the reaction;
adjusting the pH of the quenched second reaction mixture to 1 by using a 10% hydrochloric acid solution, and stirring at room temperature for 2 hours to obtain a fourth reaction mixture;
extracting the fourth reaction mixture twice with ethyl acetate and combining the organic phases;
adding anhydrous sodium sulfate into the combined organic phase, drying and filtering; and
and (3) after spin-drying the filtrate, purifying by using a chromatographic column to obtain the 2-hydroxy isopropyl substituted acetophenone.
7. The method of claim 6, wherein the purifying using the chromatography column comprises:
adding silica gel into the chromatographic column;
spin-drying the filtrate, adding ethyl acetate to dissolve the filtrate, adding silica gel, uniformly stirring, and then spin-steaming at the temperature of 30-40 ℃ to obtain a fifth reaction mixture containing the 2-hydroxyisopropyl-substituted acetophenone;
sequentially adding neutral alumina, the fifth reaction mixture and neutral alumina into the chromatographic column filled with silica gel; and
and (3) after the chromatographic column is washed by petroleum ether, washing the chromatographic column by using at least one washing liquid, and concentrating a solvent to obtain the 2-hydroxy isopropyl substituted acetophenone.
8. The method of claim 7, wherein the at least one rinse solution is selected from the group consisting of 30: 1, petroleum ether and ethyl acetate solution with the volume ratio of 20: 1, petroleum ether and ethyl acetate solution with the volume ratio of 10:1 of petroleum ether and ethyl acetate solution and the volume ratio of 5:1 petroleum ether and ethyl acetate.
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| WO2008156601A1 (en) * | 2007-06-14 | 2008-12-24 | Amgen Inc. | Tricyclic inhibitors of hydroxysteroid dehydrogenases |
| JP2015017073A (en) * | 2013-07-12 | 2015-01-29 | 株式会社クラレ | Method for producing alkyl grignard reagent using 4-methyltetrahydropyran as solvent |
| CN105037363A (en) * | 2015-07-13 | 2015-11-11 | 山东罗欣药业集团股份有限公司 | Novel synthetic method for entecavir compound |
| EP3040329A1 (en) * | 2013-08-29 | 2016-07-06 | Kyoto Pharmaceutical Industries, Ltd. | Novel aromatic compound and use thereof |
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| WO2008156601A1 (en) * | 2007-06-14 | 2008-12-24 | Amgen Inc. | Tricyclic inhibitors of hydroxysteroid dehydrogenases |
| JP2015017073A (en) * | 2013-07-12 | 2015-01-29 | 株式会社クラレ | Method for producing alkyl grignard reagent using 4-methyltetrahydropyran as solvent |
| EP3040329A1 (en) * | 2013-08-29 | 2016-07-06 | Kyoto Pharmaceutical Industries, Ltd. | Novel aromatic compound and use thereof |
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